This proposal is directed at dissecting the immunopathogenetic mechanisms of A. phagocytophilum infection in its dichotomous ability to cause mild and severe disease. We previously identified supportive data and provide preliminary studies that show the importance of NK and NKT cells in the induction of inflammatory disease. Moreover, studies in mice and humans both provide evidence of macrophage activation and hemophagocytic syndrome-like processes as the potential basis of inflammatory tissue injury and severe disease. Since macrophage activation and hemophagocytic syndromes are biologically linked to defective cytotoxic cell responses that lack the ability to dampen and resolve inflammation, we propose here to study whether A. phagocytophilum infection induces defects in direct cell killing by cytotoxic cells such as NK, NKT, and CD8 T lymphocytes, yet does not alter the profile of induced proinflammatory and macrophage activating cytokines. We expect to study this by in vitro analyses using purified cells and bacteria as a highly defined and controlled experimental approach and to verify the results in vivo using the mouse model we developed. We anticipate that these studies could shed light on the specific immunological abnormalities that occur with A. phagocytophilum infection and allow a more focused and intensive search for targets that could provide new opportunities for therapeutic interventions that diminish the severe consequences of infection.